TRANSGENIC MICE CARRYING A PSARAST24 HYBRID GENE DEVELOP SALIVARY-GLAND AND GASTROINTESTINAL-TRACT NEOPLASMS

BACKGROUND: Although prostate cancer is one of the most prevalent tumo rs in men, knowledge of its biology has been hindered by lack of anima l models. We have attempted to develop a prostate cancer model utilizi ng transgenic mouse technology. EXPERIMENTAL DESIGN: Two lines of tran sgenic mice were derived from one cell stage embryos injected with a f usion gene consisting of a mutated (codon 12) ras gene driven by the h uman prostate specific antigen (PSA) promoter in an attempt to target the oncogene specifically to the mouse prostate gland. Nontransgenic F VB/N mice were used as controls, The animals were sacrificed for study between 4 and 55 weeks of age. RESULTS: All organs were normal except the salivary glands and gastrointestinal tracts, both of which develo ped carcinomas in animals older than 44 weeks. The salivary gland tumo rs were of ductal origin, exhibited a variable degree of differentiati on, and were shown to contain abundant PSAras mRNA by in situ hybridiz ation. The gastrointestinal tract tumors were undifferentiated but app eared to be of stromal origin. Both salivary gland and gastrointestina l tumors occasionally metastasized. No transgene expression could be d emonstrated in the prostate gland by either reverse transcription-poly merase chain reaction or in situ hybridization. CONCLUSIONS: Lack of t ransgene expression by the prostate can be explained on the basis of t he apparent species specificity previously observed for PSA. Expressio n in salivary gland is best attributed to identity between the nucleot ide sequences of the PSA promoter and of a mouse glandular kallikrein normally secreted by the salivary gland.